Genital infection by genus alpha human papillomavirus (HPV) types is the necessary cause of cervical cancer and a large proportion of vulvar carcinomas. Accumulating evidence suggests that genus beta HPV types contribute to the development of squamous cell skin carcinoma (SCSC), particularly in organ transplant recipients (OTR). Although the molecular mechanisms through which HPV oncoproteins influence the development of anogenital and SCSC differ, an immunologic milieu that allows the virus and/or nascent tumor cells to escape host surveillance likely plays a key role in the etiology of these cancers. Our long-term goal is to clarify the role of immunogenetic factors in the etiology of HPV-related cancers. In the first specific aim, we will test the hypothesis that the risk of cervical and vulvar carcinoma is increased among persons carrying variant alleles of genes involved in the Toll-like receptor (TLR) pathway (TLR3, TLR4, TLR7, TLR9, TICAM1, T1CAM2, TIRAP, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), a key component of the innate immune response. This aim will use resourcesDNA specimens and interview data from population- based cases of squamous cell cervical cancer (n=391), cervical adenocarcinomas (n=508), squamous cell vulvar carcinomas (n=535), and population controls (n=1,318)accumulated in the prior funding periods of the Program Project Grant. In the second specific aim, we will test the hypothesis that the risk of SCSC in OTR is increased among persons carrying variant alleles of genes involved in the immune response to HPV, tumor antigens, and/or UV light: human leukocyte antigen (HLA) (DRB1, DQB1, A, B, C, and G); TLR pathway (TLR4, TLR7, TICAM1, TICAM2, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), immunomodulatory cytokines (IL10, IL12A, IL12B, IL6, IFNG and TNF), and nucleotide excision repair enzymes (XPB, XPC, XPD, XPF, XPG, and ERCC1). This aim will use DNA specimens and other data obtained from 250 SCSC cases and 250 controls recruited into Project 1. For the candidate genes other than the classical HLA-DRB1-DQB1, -A, -B, -C loci, we will capture the major patterns of genomic variation by choosing and assaying for tagging single nucleotide polymorphisms (tagSNPs). Analytic methods for multilocus genotype data will be used to estimate the associations with individual polymorphisms and inferred haplotypes. This project will provide new information about the role of inherited variation in immune response systems in the development of HPV-related cancers. LAY SUMMARY: Infection with cancer-causing human papillomaviruses (HPV) is common, but many infected persons do not develop cancer. This study will determine whether a person's genetic make-up influences whether HPV-related cancers occur, and could provide clues as to how such cancers might be prevented in the future.